Cul3regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development

Abstract

11De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to 12 autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the 13 consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice 14 exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. 15Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration 16 and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal 17 columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous 18 excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative 19 proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance 20 in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells 21 results in atypical organization of the actin mesh at the cell leading edge, likely causing the 22 observed migration deficits. In contrast to these important functions early in development, Cul3 23 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in 24 adult mice does not result in the behavioral defects observed in constitutive Cul3 25